Alkaptonuria and Homogentisic Acid Oxidase

Alkaptonuria (AKU)

• Caused by a deficiency of homogentisic acid oxidase, leading to the accumulation of homogentisic acid (HGA)
• HGA oxidase is found only in the liver and kidney, and plays a crucial role in the catabolism of phenylalanine and tyrosine

Etiology and Pathophysiology

• Inherited as an autosomal recessive trait, with consanguinity noted by Garrod
• A rare disorder affecting about 1 in 250,000 live births
• Deficiency of homogentisate dioxygenase leads to the accumulation of HGA and its oxidized derivative, benzoquinone acetic acid
• This can be polymerized to form a dark pigment, deposited in connective tissue

Clinical Abnormalities

• Urine from AKU patients darkens when exposed to air, especially if alkalinized
• Patients usually excrete acid urine of normal color, which turns dark on standing
• Infants may be recognized due to their cloth diapers turning black or brown when washed with alkaline soap or detergent
• Patients develop visible pigmentation (ochronosis) of the sclerae or cartilage of the ears after 30 years of age
• Pigment may also be seen in the corneal, buccal mucosa, nails, and skin
• Patients develop pain in weight-bearing joints, especially after 30 years of age
• Joint-replacement surgery may be necessary at a relatively young age
• Patients may become bedridden due to severe limitation of movement

Epidemiology

• Worldwide prevalence of AKU is 1 case in 250,000 births
• As of now, 950 AKU sufferers have been identified in 40 countries
• More prevalent in Slovakia, the Dominican Republic, India, and Jordan
• Highest prevalence is in Slovakia, where up to 1 in 19,000 are affected

Investigation and Diagnosis

• Diagnosis can be confirmed or excluded by collecting urine for 24 hours and determining the amount of HGA using HPLC or specific enzymatic methods

Treatment and Outcomes

• Recommended treatments include large doses of ascorbic acid (vitamin C) or dietary restriction of amino acids phenylalanine and tyrosine
• Nitisinone may be effective in treating AKU, by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase and blocking the production of HGA
• Low-dose nitisinone (2 mg/day) has been shown to reduce plasma and urine HGA by 95%